Fluorescent Probes for Imaging Reactive Cell Metabolites
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Embargo End Date
ICR Authors
Authors
Bayley, C
Document Type
Thesis or Dissertation
Date
2025-01-03
Date Accepted
Abstract
This thesis reports the design and development of activity-based sensors (ABS) form vitro imaging of reactive oxygen (ROS) and nitrogen species (RNS). The ABS have been designed on
established boronic pinacol ester sensing moieties and a range of reporters including: 4-nitroaniline, 4-methyl-7-amino-coumarin, and 1,8-naphthalimide. Chapter 1 includes: a thesis introduction,
background to reactive intracellular metabolites such as hydrogen peroxide and peroxynitrite,
current methods of ROS/RNS imaging, fluorescence imaging, and a history of activity-based
sensing. Chapter 2 comprises an in-depth investigation into known and novel proof-of-concept
based ABS. their synthesis, and all non-biological fluorescence testing, including the selectivity,
stability. and sensitivity of such compounds. Chapters 3 and 4 include two strategies to enhance the intracellular retention time of fluorescent reporters for ABS. The first hypothesis for improving the intracellular retention time of reporters relies on lowering passive permeability, a concept termed ''the polarity switch". This chapter investigates the entrapment of positively charged reporters
unmasked via ROS/RNS mediated mechanisms. The second strategy and the following chapter explore using covalent warheads for the promiscuous covalent attachment of ABS within the cell. This chapter also includes the design and development of a novel masked covalent warhead which is unreactive until activation by ROS/RNS. Lastly, chapter 5 includes all biological and imaging
data of the compounds generated as part of this thesis, including a discussion on the permeability and stability of ABS under biological conditions.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Medicinal Chemistry 1